Mitotic DNA damage promotes chromokinesin-mediated missegregation of polar chromosomes in cancer cells.

Abstract

DNA damage response (DDR) during interphase involves active signaling and repair to ensure genomic stability. However, how mitotic cells respond to DNA damage remains poorly understood. Supported by correlative live-/fixed-cell microscopy, it was found that mitotic cells exposed to several cancer chemotherapy compounds acquire and signal DNA damage, regardless of how they interact with DNA. In-depth analysis upon DNA damage during mitosis revealed a spindle assembly checkpoint (SAC)-dependent, but ataxia telangiectasia mutated-independent, mitotic delay. This delay was due to the presence of misaligned chromosomes that ultimately satisfy the SAC and missegregate, leading to micronuclei formation. Mechanistically, it is shown that mitotic DNA damage causes missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins. Importantly, with the exception of DNA damage induced by etoposide-a topoisomerase II inhibitor-this outcome was independent of a general effect on kinetochore microtubule stability. Colony formation assays in pan-cancer cell line models revealed that mitotic DNA damage causes distinct cytotoxic effects, depending on the nature and extent of the damage. Overall, these findings unveil and raise awareness that therapeutic DNA damage regimens may contribute to genomic instability through a surprising link with chromokinesin-mediated missegregation of polar chromosomes in cancer cells.

• Authors: Marco Novais-Cruz, António Pombinho, Mafalda Sousa, André F Maia, Helder Maiato, Cristina Ferrás
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 34 Issue 5 Pg. ar47 (05 01 2023) ISSN: 1939-4586 [Electronic] United States
• PMID: 36989031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• chromokinesin
• Nuclear Proteins
• DNA-Binding Proteins

Topics

• Nuclear Proteins (metabolism)
• DNA-Binding Proteins (metabolism)
• DNA Damage
• Chromosomes (metabolism)
• Neoplasms (genetics)